PROJECT DESCRIPTION: This STTR Phase I proposal is intended to demonstrate the feasibility of developing tanshinone small-molecule analog (TSA) 521 as an effective and safe small-molecule therapy for patients with sepsis and septic shock. In the US, more than one million people develop sepsis every year. Yet, no effective anti-sepsis treatment exists other than antibiotics and supportive care. We have discovered that high mobility group box-1 (HMGB1) is a pivotal proinflammatory mediator released by macrophages during sepsis. We have also discovered that tanshinone IIA sodium sulfonate, in high doses, decreased circulating levels of HMGB1 and improved the survival rate in the endotoxemia and cecal ligation and puncture models of sepsis. To further enhance the solubility and the binding affinity for HMGB1, we generate TSA521 by opening up tanshinone?s orthobenzoquinone and introducing a carboxylic group. The affinity of TSA521 for HMGB1 is 55-fold higher than that of the tanshinone IIA sodium sulfate. TSA521 also potently inhibits the release of proinflammatory cytokines and chemokines known to aggravate and perpetuate inflammation in sepsis. Based on these preliminary studies, we hypothesize that TSA521 can be developed as an effective and safe therapeutic agent to treat patients with sepsis and septic shock. To advance TSA521 towards its ultimate clinical use, we will identify its most effective dose and therapeutic window to attenuate organ injury and improve survival in an animal model of sepsis. We will then determine TSA521?s safety and pharmacokinetic profile. These proposed studies will provide critical feasibility information to further develop TSA521 as an HMGB1-suppressing agent to treat sepsis. Our ultimate goal is to obtain commercial utilization of TSA521 as a novel and effective treatment for patients with sepsis and septic shock.